Compounds with anti-influenza activity: present and future of strategies for the optimal treatment and management of influenza. Part I: influenza life-cycle and currently available drugs

GASPARINI, R.; AMICIZIA, D.; LAI, PL.; BRAGAZZI, NL.; PANATTO, D.

In recent times, the most widely used antivirals against influenza have been the inhibitors of Neuroaminidase: namely Oseltamivir and Zanamivir (Figs. 2, 3) . From a chemical point of view, NA inhibitors can be classified into: sialic acid derivatives (or 5,6-dihydro-4H-pyran derivatives), benzoic acid derivatives, cyclohexene derivatives, cyclopentane derivatives, pyrrolidine derivatives and natural products. The first NA inhibitors were representatives of the first chemical class, being unsaturated syalic acid analogs, such as DANA and FANA, which were initially described by Meindl and Tuppy in 1969 [223] . NA is a homotetrameric enzyme of about 220-240 kDa that is essential to the reproduction of the influenza virus. Indeed, it exerts at least three crucial actions. First, neuraminidase frees the virus from the respiratory mucus and allows it to reach the cells of the respiratory mucosa more easily. The coordinated action of HA, NA, M1 and M2 is required during the phase of viral budding. Finally, NA is required in order to release the virus from the cell surface by cutting the molecules of sialic acid that still anchor the virus to the cell surface by means of HA after completion of the replication cycle. This action also facilitates separation of the self-aggregated virions of the viral progeny. Burnet and coll. [224] first had the idea that an inhibitor of NA could be an effective antiviral agent, but only when the crystal structure of NA and its complex with neuroaminic acid were defined by Coleman in 1993 was it possible for von Itzstein [225] to synthesize a neuroaminic acid derivative with an enhanced affinity for influenza NA. This compound is Zanamivir (4-guanidino-Neu5Ac2en, or 4-GU-DANA). Its mechanism of action, which is identical to that of Oseltamivir, is characterized by the fact that the molecule mimics sialic acid; thus, it enters into competition with the acid and reversibly binds the molecules of viral NA. Zanamivir was designed to concentrate locally in the respiratory tract, while Oseltamivir (GS4104) was designed to have a high bioavalability (80%) concentration after oral administration. Indeed, Oseltamivir is very well absorbed from the gastrointestinal tract and is rapidly metabolised to active Oseltamivir carboxylate (GS4071) ([3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate) in the liver by hepatic carboxyl-esterase 1. The active metabolite is distributed throughout the body, including the upper and lower respiratory tract, middle ear, tracheal lining, nasal mucosa and lungs [226] . Plasma half-life varies from 1-2 to 3-4 hours, being 6-10 hours for the carboxylate form [226] . Oseltalmivir is extensively metabolized (more than 95%). Oseltamivir and Zanamivir result comparable in terms of clinical profile and superior to the adamantanes [227, 228] . Regarding the clinical effectiveness of the two drugs, a recent meta-analysis by Jefferson et al. [229] revealed that both drugs had a modest therapeutic effect in healthy adults and that prophylactic treatment with either Zanamivir or Oseltamivir was effective in preventing the disease. Zanamivir is supplied in "Rotadisks" with four blisters containing 5 mg of powder each. Five Rotadisks are packaged with a Diskhaler inhalation device. Oseltamivir is available as 75 mg capsules or as an oral suspension containing 12 mg/mL (Oseltamivir phosphate) [217] . ADRs are usually nausea, vomiting. Recently, CNS toxicity in infants y